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DNA interstrand crosslink repair and cancer
Andrew J.Deans* and Stephen C.West*
Abstract | Interstrand crosslinks (ICLs) are highly toxic DNA lesions that prevent transcription and replication by inhibiting DNA strand separation. Agents that induce ICLs were one of the earliest, and are still the most widely used, forms of chemotherapeutic drug. Only recently, however, have we begun to understand how cells repair these lesions. Important insights have come from studies of individuals with Fanconi anaemia (FA), a rare genetic disorder that leads to ICL sensitivity. Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance.
The use of DNA interstrand crosslinking agents as a tool for chemotherapy was born out of the horror of the use of chemical weapons in the Second World War. In December 1943, the US Merchant Ship S.S. John Harvey, which was anchored in the Italian harbour of Bari, was bombed in a German air raid. On board was a secret and deadly cargo of around 60 tonnes of sulphur mustard bombs, which detonated and contaminated the nearby city and surrounding area. After the ensuing chaos had passed, physicians carrying out autopsies noticed that the chemical had specifically attacked the victims white blood cells. With great insight, they hypothesized that these chemicals could have a more righteous action: for the treatment of leukaemia. In 1946, after the barbarity of the war had past, the first publication of Nitrogen Mustard Therapy appeared1.
Sixty-eight years and a few chemical modifications later nitrogen mustards such as http://www.cancer.gov/drugdictionary?CdrID=39748
Web End =cyclophosphamide and http://www.cancer.gov/drugdictionary?CdrID=42973
Web End =melphalan are still front-line chemotherapeutic agents in the treatment of leukaemia, as well as solid tumours. Nitrogen mustards were joined in the clinical treatment of cancer by mitomycin C (http://www.cancer.gov/drugdictionary?CdrID=42674
Web End =MMC ) in 1956, platinum compounds such as http://www.cancer.gov/drugdictionary?CdrID=39515
Web End =cisplatin in 1971 and psoralens in 1989. Although these drugs all showed remarkable anti-cancer properties, it was not known that they function by inducing interstrand crosslinks (ICLs) until well...